Gliomas are the most common and deadly brain tumors in adults and can arise from mutant oligodendrocyte progenitors by a largely unknown mechanism. Specific treatments to eliminate these malignant OPC have not been developed, primarily because the underlying mechanisms associated with their malignant transformation are not well understood. The goal of this proposal is to find the underlying causes for malignant transformation of OPC by investigating defects in asymmetric cell division and to test specific pharmacological agents targeted to re-store these defects for their ability to impact tumor growth. We have recently provided first molecular evidence that oligodendrocyte progenitors divide asymmetrically to self-renew and generate mature oligodendrocytes by showing that the transmembrane proteoglycan NG2 distributes asymmetrically during mitosis and thereby promotes activation of epidermal receptor growth factor and self-renewal and prevents differentiation of the NG2+ progeny. Oligodendrocyte progenitors with defective NG2 asymmetry aberrantly self-renew, fail to differentiate and turn into glioma - initiating cells. We hypothesize that losing cellular asymmetry transforms oligodendrocyte progenitor cells, by disrupting self-renewal and differentiation. Our preliminary results indeed show that enforcing a block of asymmetric cell division by removing expression of conserved asymmetry regulator Lethal giant larvae, LGL1, in oligodendrocyte progenitors causes tumor formation. Moreover, pharmacological inhibition of Plk1, a conserved regulator of asymmetric cell division, re-stores NG2 asymmetry in malignant, glioma- initiating cells. Guided by such strong preliminary data, we have three specific aims: In the first aim, we determine whether oligodendrocyte progenitor-specific loss of LGL1 causes NG2-dependent tumor- initiation. To fulfill this aim, we propose to generate oligodendrocyte progenitors and oligodendrocyte progenitor precursor deficient for LGL1 alone and co-deficient for LGL1 and NG2, in mouse models using a CRE-LOX approach. The analysis of tumor formation in these models will enable us to distinguish between NG2-dependent and - independent functions of LGL1 in tumor initiation. In the second aim, we will determine a causal link of loss of LGL1, disrupted NG2 asymmetry and tumor initiation in OPC. We will test LGL1-/- oligodendrocyte progenitors for defects in NG2 asymmetry, self-renewal and differentiation. To link losing LGL1 and NG2 asymmetry to malignant transformation, we will evaluate the malignant potential of LGL1-/- and test whether co-deletion of NG2 ameliorates tumor formation and re-expression of symmetric, ectopic NG2 enhances defects in LGL1-/- OPC. In the third aim, we will investigate the pharmacological modulation of asymmetric cell division for its impact on tumor growth. Our goal is to prove that loss of asymmetric cell division is causal to tumor initiation and thereby evaluate novel therapeutic approaches that re-store asymmetric cell division to malignant progenitors and for their potential to impact tumor growth.